The long-term goal of this grant project is to understand the mechanisms of eosinophilic inflammation in human diseases. Airway inflammation in patients with asthma is characterized by airway eosinophilia and increased numbers of lymphocytes producing Th2-type cytokines. However, the immunological mechanisms to explain the associations among genes, environment and Th2-type inflammation in asthma are not well understood. We recently found that when mice are exposed to an environmental allergen, IL-33 is released quickly to the airways. Administration of exogenous IL-33 promotes airway eosinophilia and development of antigen- specific Th2 CD4+ T cells. We have also identified in mouse lungs a novel lymphoid cell that expresses no lineage markers, but distinctly expresses CD25, CD44, IL-7R, and Sca-1. This cell responds quickly and vigorously to IL-33 and produces large quantities of IL-5, IL-9 and IL-13. Therefore, we hypothesize that when the respiratory tract is exposed to airborne environmental allergens, this novel lymphoid cell in the lungs [referred herein as the lung innate helper (LIH) cell] is involved in both innate and adaptive Th2 immune responses and airway pathologic changes. Our renewal application will test this hypothesis. In Aim 1, we will determine the proliferation and functions of LIH cells in response to lung-derived cytokines, such as IL-33, TSLP, and IL-25. We will investigate the regulation of LIH cells and how IL-33- stimulated LIH cells are involved in innate Th2-type airway inflammation and in the development of antigen- specific Th2 CD4+ T cells. In Aim 2, we will determine the roles of IL-33, TSLP and LIH cells in allergen- induced Th2-type airway inflammation. We will investigate the roles of these molecules and cells in acute and chronic asthma models in mice exposed to environmental allergens. In Aim 3, we will investigate the frequency and functions of the innate lymphoid cells that are analogous to the LIH cell in human asthma. We will collect peripheral blood specimens from severe asthma patients and from control individuals and examine whether IL-33-responsive LIH-like cells are increased and/or functionally activated in patients with asthma. We have developed robust mouse models to dissect the innate and adaptive Th2-type immune responses to environmental allergens. All the tools necessary to accomplish the project, including gene- deficient mice and adoptive cell transfer model, are currently available in our laboratory. An outstanding group of investigators, including an asthma specialist, will also participate. Therefore, the proposed studies are likely to provide fundamental information regarding the mechanisms by which Th2-type immune responses and airway inflammation develop after exposure to environmental allergens. They will provide a new understanding of the pathogenesis of asthma and will lead to the development of novel treatments and prevention strategies for asthma and other Th2-type airway inflammatory disorders.